The identification of agents that can either treat or halt the spread of smallpox or other diseases caused by orthopox viruses would have great benefit in mitigating the risk of the smallpox virus being used as a biological weapon. Furthermore such agents would be useful as a therapeutic for accidental exposure to other orthopox viruses such as the recently publicized cases of monkeypox caused by human exposure to exotic imported animals. The ideal therapeutic would be an effective and safe orally available small molecule that could be taken by individuals who were exposed to an orthopox virus or had active disease. Recent evidence suggests that the proteolytic activity of a novel protease encoded by the orthopox virus genome is an obligatory event for viral proliferation. Using a proprietary process of drug discovery called TTP Translational Technology (tm) that combines novel medicinal chemistry with computer modeling and a series of in vitro biological screening assays, TransTech Pharma has discovered small molecule inhibitors of the orthopox protease that have drug like characteristics in terms of potency, safety and pharmacokinetic characteristics. In this grant, we propose to identify a compound with efficacy in A) an in vivo Mouse Model of Vaccinia Virus, a related pox virus, B) other orthopox virus disease relevant animal models, C) perform IND enabling toxicology studies including the associated pharmaceutical development necessary to generate drug substance to perform this study. Upon successful completion of the proposed milestones related to this grant, we anticipate performing clinical trials with a novel small molecule to treat smallpox infection.